The present application concerns a prefilled single-dose syringe featuring a barrel open at at least one of its ends and provided with a narrowed-diameter portion neighboring this end; a stoppering device fitted into the barrel to stopper said narrowed-diameter portion, which stoppering device is movable axially between a first position, called the storage position, and a second position, called the injection position, and featuring an internal tube; and a nozzle attached to this stoppering device, fitted onto the shank of the open end of the barrel and provided with a ferrule equipped with an axial channel, which axial channel is intended to communicate with the internal tube of the movable stoppering device when it is moved into its second position.
There already exist a large number of prefilled syringes that are made up of a body or barrel containing the medicine to be injected into the patient, a movable plunger inside of this barrel, a needle attached to one of the ends of the barrel, and a cap that protects the barrel and ensures its airtightness. Such an existing device is illustrated, for example, by Swiss Pat. No. 571 858. It is currently still used a great deal because it does not require decanting and because the single dose is guaranteed by the manufacturer.
However, even if the syringe should, in principle, be thrown away, it remains reusable, and there is nothing to guarantee, if not for a tamper-proof original packaging, that the syringe contains a proper medicine. The fact that the airtightness is ensured by the cap, which contains air, constitutes another disadvantage of this device. Furthermore, the ampul requires costly testing after filling and after the plunger is put in place.
To overcome these various drawbacks was proposed a syringe of the ampul-syringe type, described in European Patent Application No. 83112127.2 filed by the applicant, regarding a barrel containing a medicine under pressure, the opening of which is stoppered by a stoppering device that forms a unit with a nozzle, equipped with an attachment ferrule, an injection needle, and a tube capable of putting the interior of the body of the syringe in communuication with the needle; both the nozzle and the stoppering device attached to it are movable between a stoppered position and an in-use position.
This principle of stoppering by means of a nozzle could have been adapted for a syringe of a different type, comprising a body and a plunger to slide axially inside the body, as well as for a double-compartment syringe or mixing syringe that consists of two plungers serving two chambers containing, initially, two different respective products intended to be mixed before they are injected. This latter device, for example, is described in the applicant's European Patent Application No. 83113098.4.
The manual or automatic testing mentioned earlier of ampuls containing medicines to be injected, with the intention of detecting the possible presence of solid particles in the medicine contained in the ampul, proves to be relatively costly for the manufacturer. This testing is responsible for a not negligible precentage of the production costs of the product, due to the fact that it requires a testing station, the installation and operating costs of which are high.
In addition, the losses due to unacceptable finished products have a negative influence on the cost price of sales of acceptable products.
Although this testing, performed by the manufacturer at great expense, theoretically permits the arrival at a product that is considered acceptable---that is, of which at least 90% or 95% is greater than 50 micrometers--free of any solid particles, the practical reality is quite different because storage, on the one hand, and the manipulations required before using the product, on the other, may alter its quality considerably. In effect, during storage certain products may produce solid deposits, which are not entirely dissolved after shaking prior to injection. In the mixing syringes, the powder of freeze-dried medicines is not always dissolved completely by the solvent in such a way that the risk of injecting solid residues is not nonexistent. When the medicine is contained in an ampul the neck of which must be broken to free the product, very small particles of broken glass are often mixed in with the liquid to be injected.
When the medicine is in a container stoppered by a rubber cork that must be pierced with a needle before removing or injecting the liquid medicine, particles of synthetic material, especially elastomers, may be found in the liquid and risk being injected into the patient's body.
The problems cited above are well known by the specialists, but until now no completely satisfactory solution has been found--that is, a solution that permits both elimination of the expensive testing by the manufacturer and, at the same time, elimination of the risk of injecting solid particles into the patient's body.
The article "Glass Embolism", published in the journal The Lancet of Dec. 16, 1972, page 1300, raises the problem of particles of cotton, rubber, synthetic materials, glass, or other solid matter present in doses for intravenous injection; mentions the clinical consequences likely to be provoked in the patient; and proposes a solution, consisting of performing the filling of the containers in a pressure chamber.
The article "Glass Particles in Intravenous Injections", published in the periodical The New England Journal of Medicine of Dec. 7, 1972, page 1204, raises the problem of the introduction of glass particles into the human body during intravenous injections and suggests filtering the medicine by means of a filtration device marketed by the company Millipore. This device involves a filtering insert comprised of a housing containing a filtering membrane and supplied with an entry mouthpiece and an exit ferrule arranged on both sides of the membrane. This insert is intended to be mounted between a syringe and the injection needle in such a way that the liquid to be injected must pass through a filtering membrane. Its cost very often constitutes an obstacle to its general use. Furthermore, even if its use is recommended, putting it in place may be intentionally or unintentionally omitted by the health care personnel.
Finally, because this insert is intended to be used with any syringe containing any medicine to be injected, it must meet very broad criteria, especially to adjust to difference in volume and to different viscosities and to be compatible with all medicines of any kind.
The article "Residues in Antibiotic Preparations: I. Scanning Electron Microscopic Studies of Surface Topography" published in the periodical American Journal of Hospital Pharmacy (vol. 33) of May 1976, pages 433-443, treats the problem of the pathological consequences of the injection of solid particles present in antibiotic solutions supposed to be pure according to pharmaceutical standards.
The article "Particulate Contamination in Intravenous Fluids: Nature, Origin, and Hazard", published in the periodical Pharmaceutical Journal of Mar. 3, 1973, also analyzes the clinical consequences of the injection of particles with medicines injected intravenously.
The article "Foreign Bodies in Contrast Media for Angiography", published in the periodical American Journal of Hospital Pharmacy (vol. 34) of July 1977, pages 705-708, describes the analysis work performed on liquids intended for intra-arterial injections for radiological examinations, analyses that revealed the presence of contaminating particles, especially tiny glass fragments of a diameter ranging from 0.5 micrometers to 450 micrometers. The author concludes by saying that these foreign particles must be eliminated as much as possible.
The article "Coring of Rubber Closures", published in the periodical The Pharmaceutical Journal (no. 224) of Feb. 1980, page 120, raises the problem of the presence of particles of rubber in solutions to be injected. The author estimates that these particles generally originate from the technique of piercing the stopper corks of ampuls containing the products and points out that the consequences on the circulatory system of the patient are still not well known.
The article "A Foreign Matter Affair: The Problem of Particles", published in the periodical The American Journal of Intravenous Therapy, pages 23-32, summarizes the experiments that had been performed on animals to analyze the clinical consequences of the injection of solid particles of cotton, glass, rubber, synthetic matter, etc., into the vascular system. The author concludes the article by pointing out that there are numerous cases of contamination and that despite the measures already undertaken, technical progress is essential to try to bring the effective purity of injected medicine as close as possible to 100%.
All these articles in the medical literature clearly demonstrate that the presence of solid particles of any kind in injectable medicines constitutes a not-to-be neglected danger to the ill person and that at present no economically visable means has permitted the elimination of this risk without exaggeratedly increasing the cost of the treatment given.
The present application proposes to alleviate the drawbacks mentioned above by proposing a system that permits the elimination of the costly traditional testing performed by the manufacturer; avoids any contamination of the medicine to be injected by solid particles of glass or rubber usually introduced during the manipulations preceding injection; and guarantees the absence in the liquid actually injected of any air bubble or any solid particle of whatever origin, the diameter of which is larger than a specific size.
To this end, the syringe in this application is distinguished by the fact that it features at least one membrane microfilter inserted between the internal tube of the movable stoppering device and the axial channel of the ferrule of the nozzle connected to this movable stoppering device.
One could object that there already exist syringes containing a filter, such as, for example, those covered by U.S. Pat. No. 4,365,626. These syringes are, in fact, comprised of an ampul, the ends of which are stoppered by two elastomer corks, and a needle-carrying ferrule equipped with a double needle, one of which is intended for piercing one of the stopper corks of the ampul, and a filter, the intention of which is to catch particles of rubber ripped away when the cork is pierced. However, it is to be noted that the filter is of a piece with the needle-carrying ferrule mounted on the ampul just before the syringe is to be used; that it is, by this fact, an accessory element that could perhaps be replaced by another needle not equipped with a filter; and that it does not fulfill its role with repect to a total guarantee of an absence of solid particles in the liquid to be injected cited above. Moreover, the filter described--housed in a complex support structure that also carries the needle that pierces the stopper cork--is essentially intended to eliminate contamination that arises during this piercing. Finally, in light of the number of parts making up the system, the cost of production of the syringe described is so high that there could be no question of applying it as a universal system for the industrial nations and certainly not adaptable to the medical conditions encountered in certain economically disadvantaged nations.
One could also object that there exist syringes equipped with a so-called in-depth filter, such as those covered by the French Patent issued under No. 2, 361 121, comprising a syringe body provided with a plunger and stoppered at one end by a stoppering device. The needle-carrying nozzle is equipped with a deep filter intended, as before, to catch particles that might have been torn away from the elastomer membrane during its piercing.
The in-depth filters are usually made of a kind of pad made out of a variety of material, such as, for example, sintered metal or some other suitable material, which provides a collection of microtubules, the width of which is deemed to be sufficiently narrow to catch undesirable solid particles. Nevertheless, in-depth filters do not permit guaranteeing a lower limit of filtration of 100%. Actually, if statistical trials permit confirmation that such type of in-depth filters filter out, for example, 80% of particles with a diameter equal to or greater than 50micrometers, this does not exclude the possibility that several paraticles of much larger diameter--for example, particles measuring 150 micrometers--might find their way through and ultimately find their way into the filtered liquid.
The membrane microfilters, on the other hand, permit absolute means of guaranteeing 100% filtration of any solid particles the diameter of which is greater than the nominal diameter of the pores of the filter. The diameter of the pores is established by the manufacturer and can be verified by the existing techniques called "bubble point". The membrane microfilter is the equivalent of a strainer, all the openings of which are identical and determined by its construction.
In a preferred design, the membrane microfilter of the prefilled syringe in this application has pores the largest diameter of which is between 0.2 and 5 micrometers. The materials used for the manufacturer of this microfilter are preferably selected from the following substances: polyamides, acrylic copolymers covered with nonwoven polyamide, cellulose esters, polytetrafluorethylene, polypropylenes.